Marine Algal Bioactivities 129
ductal breast epithelial tumour (T47D) and human colon carcinoma (HT29) cell lines (IC 50 of 27.94 and
70.41 μg/mL; Khanavi et al. 2012).
Algae extracts have also showed promising preliminary results, although the final goal would
always be to identify the bioactive compound(s). Ethyl acetate extracts from Colpomenia sinuosa,
Halimeda discoidea, and Galaxaura oblongata inhibited the growth of human hepatoma HuH-7 cells and
leukaemia U937 and HL-60 cells in a time- and dose-dependent manner (Huang et al. 2005). The extracts
induced apoptosis of U937 and HL-60 cells as evaluated by detection of hypodiploid cells using flow
cytometry and observation of condensed and fragmented nuclei in algae extract-treated cells. However,
the antioxidant N-acetylcysteine effectively blocked algal extract-induced apoptosis, suggesting that the
extracts induced apoptosis in human leukaemia cells through the generation of ROS (Huang et al. 2005).
The hexane fraction of Sargassum swartzii and Cystoseira myrica showed selective cytotoxicity against
proliferation of Caco-2 cells (IC 50 < 100 μg/mL) and T47D cell line (IC 50 < 100 μg/mL), respectively,
increasing apoptosis in these cells (Khanavi et al. 2010).
Marine algae are thus prolific producers of biologically active secondary metabolites with cytotoxic
chemicals. Global research towards the discovery of novel and clinically useful antitumoural agents
derived from marine organisms continues at a remarkably active pace.
In vivo anti-cancer activity
Suffness and Douros (1982) posited that the terminology with reference to in vitro and in vivo anticancer
activity had been used too loosely. Many compounds cited as anticancer or antitumoural agents are in fact
only cytotoxic to tumour cells in vitro and may not display particular selectivity towards tumour cells as
opposed to non-tumoural cells. For that reason, the authors have suggested that the term “cytotoxicity”
means toxicity to tumour cells in in vitro cell cultures. Thus, the terms “antitumoural” or “antineoplastic”
should not be used to express results of in vitro assays; rather it should refer to data of in vivo trials with
animal models exclusively. In addition, the term “anticancer” should be reserved for reporting clinical
trials data in humans.
The Food and Drug Administration (FDA) is the federal agency responsible for the approval of all
drugs commercialized in the United States. The FDA has established an approval protocol that implies
several drug trials, grouped in stages. The first stage involves in vitro and animal testing. Only if adverse
side effects are not observed should the testing proceed to the second stage, where human subjects are
subjected to clinical trials. In the clinical trials stage, compounds are typically submitted to four phases.
In Phase I, researchers gather preliminary information on the chemical action and safety to find a safe
testing dose in a small group of people. In Phase II trials, the experimental treatment is given to a larger
group of subjects to provide knowledge on the efficacy of the drug and additional information on its
safety. In Phase III trials, the treatment is given to large groups of people (1000–3000) to confirm its
effectiveness, monitor side effects, compare it to commonly used treatments, assess dosage effects, and
collect further information that will allow it to be safely used. In Phase IV trials, post-marketing studies
delineate additional information, including the risks and benefits of the treatment as well as the optimal
use of the novel drug (Meinert 2006). However, one has to take into account that going through all the
steps of this protocol can take several years in order to verify whether treatment generates long-term side
effects.
Kahalalide F is a marine natural product and an anticancer drug candidate in clinical development at
PharmaMar (Hamann and Scheuer 1993). This cyclic depsipeptide (of the family of dehydroaminobutyric)
was isolated from the sea slug Elysia rufescens but is most probably derived from Bryopsis sp., its
green algal diet (reviewed by Varela et al. 2013). E. rufescens is able to sequester algal chloroplasts,
which synthesize secondary metabolites. The compound has shown antitumoural activity, probably by
interfering with lysosome function in prostate, colorectal, and lung cancer cell lines as well as in animal
models of lung and breast cancer (García-Rocha et al. 1996; Suárez et al. 2003). The evidence of in vivo
activity in experimental human cancer models of androgen independent prostate cancer and other solid
tumours established a rationale to implement a clinical program with this innovative compound. A phase
I trial investigating the feasibility of a weekly schedule with kahalalide F given as a 1-hour intravenous
ductal breast epithelial tumour (T47D) and human colon carcinoma (HT29) cell lines (IC 50 of 27.94 and
70.41 μg/mL; Khanavi et al. 2012).
Algae extracts have also showed promising preliminary results, although the final goal would
always be to identify the bioactive compound(s). Ethyl acetate extracts from Colpomenia sinuosa,
Halimeda discoidea, and Galaxaura oblongata inhibited the growth of human hepatoma HuH-7 cells and
leukaemia U937 and HL-60 cells in a time- and dose-dependent manner (Huang et al. 2005). The extracts
induced apoptosis of U937 and HL-60 cells as evaluated by detection of hypodiploid cells using flow
cytometry and observation of condensed and fragmented nuclei in algae extract-treated cells. However,
the antioxidant N-acetylcysteine effectively blocked algal extract-induced apoptosis, suggesting that the
extracts induced apoptosis in human leukaemia cells through the generation of ROS (Huang et al. 2005).
The hexane fraction of Sargassum swartzii and Cystoseira myrica showed selective cytotoxicity against
proliferation of Caco-2 cells (IC 50 < 100 μg/mL) and T47D cell line (IC 50 < 100 μg/mL), respectively,
increasing apoptosis in these cells (Khanavi et al. 2010).
Marine algae are thus prolific producers of biologically active secondary metabolites with cytotoxic
chemicals. Global research towards the discovery of novel and clinically useful antitumoural agents
derived from marine organisms continues at a remarkably active pace.
In vivo anti-cancer activity
Suffness and Douros (1982) posited that the terminology with reference to in vitro and in vivo anticancer
activity had been used too loosely. Many compounds cited as anticancer or antitumoural agents are in fact
only cytotoxic to tumour cells in vitro and may not display particular selectivity towards tumour cells as
opposed to non-tumoural cells. For that reason, the authors have suggested that the term “cytotoxicity”
means toxicity to tumour cells in in vitro cell cultures. Thus, the terms “antitumoural” or “antineoplastic”
should not be used to express results of in vitro assays; rather it should refer to data of in vivo trials with
animal models exclusively. In addition, the term “anticancer” should be reserved for reporting clinical
trials data in humans.
The Food and Drug Administration (FDA) is the federal agency responsible for the approval of all
drugs commercialized in the United States. The FDA has established an approval protocol that implies
several drug trials, grouped in stages. The first stage involves in vitro and animal testing. Only if adverse
side effects are not observed should the testing proceed to the second stage, where human subjects are
subjected to clinical trials. In the clinical trials stage, compounds are typically submitted to four phases.
In Phase I, researchers gather preliminary information on the chemical action and safety to find a safe
testing dose in a small group of people. In Phase II trials, the experimental treatment is given to a larger
group of subjects to provide knowledge on the efficacy of the drug and additional information on its
safety. In Phase III trials, the treatment is given to large groups of people (1000–3000) to confirm its
effectiveness, monitor side effects, compare it to commonly used treatments, assess dosage effects, and
collect further information that will allow it to be safely used. In Phase IV trials, post-marketing studies
delineate additional information, including the risks and benefits of the treatment as well as the optimal
use of the novel drug (Meinert 2006). However, one has to take into account that going through all the
steps of this protocol can take several years in order to verify whether treatment generates long-term side
effects.
Kahalalide F is a marine natural product and an anticancer drug candidate in clinical development at
PharmaMar (Hamann and Scheuer 1993). This cyclic depsipeptide (of the family of dehydroaminobutyric)
was isolated from the sea slug Elysia rufescens but is most probably derived from Bryopsis sp., its
green algal diet (reviewed by Varela et al. 2013). E. rufescens is able to sequester algal chloroplasts,
which synthesize secondary metabolites. The compound has shown antitumoural activity, probably by
interfering with lysosome function in prostate, colorectal, and lung cancer cell lines as well as in animal
models of lung and breast cancer (García-Rocha et al. 1996; Suárez et al. 2003). The evidence of in vivo
activity in experimental human cancer models of androgen independent prostate cancer and other solid
tumours established a rationale to implement a clinical program with this innovative compound. A phase
I trial investigating the feasibility of a weekly schedule with kahalalide F given as a 1-hour intravenous